DESCRIPTION (Verbatim from the application): The long term objective of my investigation is to elucidate the alteration of endothelial mechanisms that elicit an increase the arteriolar tone in hypertension. It is a unique feature of arterioles, that they can change their diameter in response to changes in hemodynamic forces. These forces stimulate mechanisms in the endothelium and smooth muscle, which in turn regulate the diameter and consequently pressure, wall shear stress and blood flow. We propose that hypertension impairs these mechanisms which then contribute to increased peripheral resistance. The causes for the development of hypertension are largely unknown. I propose several approaches which will help to reveal, arteriolar mechanisms so far unknown which could contribute to the development of high peripheral resistance provoking increases in blood pressure. Knowing these mechanisms will help to develop evidence-based, novel therapies. The overall hypothesis is that changes in the endothelial and smooth muscle [Ca2+]i (and/or sensitivity) and synthesis of reactive oxygen species are responsible for the high intraluminal pressure- and/or angiotensin II-induced alterations of myogenic and flow dependent mechanisms of arterioles in hypertension, by enhancing the release of constrictor (PGH2/TxA2, endothelin) and reducing the release of dilator factors (NO, EDHF) from the endothelium. This project has three Specific Aims: 1. To determine the role of endothelium-derived PGH2/TxA2 and endothelin in the control of intracellular Ca2+ level and/or Ca2+ sensitivity of arteriolar smooth muscle leading to the upregulation of myogenic mechanism in hypertension. 2. To determine the role and mechanisms of high intra-arteriolar pressure (Pi)- and/or angiotensin II-induced increased synthesis of reactive oxygen species (ROS) that impairs responses to NO-mediated agonists and flow dependent dilations and to identify the cellular source(s) of ROS. 3. To determine the effect of NO and EDHF on arteriolar smooth muscle [Ca2+]i , as well as the association between changes in endothelial [Ca2+]i, NO and EDHF release to acetylcholine and increases in flow in arterioles of normotensive and hypertensive rats.